Novel facets of glioma invasion

Malignant gliomas including Glioblastoma (GBM) are characterized by extensive diffuse tumor cell infiltration throughout the brain, which represents a major challenge in clinical disease management. While surgical resection is beneficial for patient outcome, it is well recognized that tumor cells at the invasive front or beyond stay behind and constitute a major source of tumor recurrence. Invasive glioma cells also represent a difficult therapeutic target since they are localized within normal functional brain areas with an intact blood brain barrier (BBB), thereby excluding most systemic drug treatments. Cell movement is mediated via the actin cytoskeleton where corresponding membrane protrusions play essential roles. This review provides an overview of the various paths of glioma cell invasion and underlines the specific aspects of the brain microenvironment. We highlight recent insight into tumor microtubes, neuro-glioma synapses and tumor metabolism which can regulate collective invasion processes. We also focus on the deregulation of actin cytoskeleton-related components in the context of glioma invasion, a deregulation that may be controlled by genomic alterations in tumor cells as well as by various external factors, including extracellular matrix (ECM) components and non-malignant stromal cells. Finally we critically assess the challenges and opportunities for therapeutically targeting glioma cell invasion.